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1.
J Photochem Photobiol B ; 203: 111771, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31911399

RESUMO

Ultraviolet B (UVB) radiation triggers the activation of many reactive oxygen species (ROS)-sensitive signaling pathways, resulting in the induction of skin damage that can progress to premature skin aging with long-term exposure. Even after the cessation of UVB radiation, the activated photosensitizers can still cause cellular injury. Thus, the use of photoprotectors that inhibit or prevent intracellular ROS production during or after UV exposure is one alternative to counteract UV-induced oxidative damage. The present study investigated the photoprotective activity of protocatechuic acid (P0) and its alkyl esters ethyl protocatechuate (P2) and heptyl protocatechuate (P7) against UVB-induced damage in L929 fibroblasts by evaluating biomarkers of oxidative stress and photoaging. P0, P2 and P7 markedly increased cell viability after UVB exposure. This protective effect was related to the ability of these compounds to absorb UVB and restore cellular redox balance even 24 h after UVB exposure. P0, P2 and P7 also decreased oxidative damage to membrane lipids, mitochondrial membrane potential, and DNA. They also inhibited the nuclear translocation of NF-κB p65 and downregulated the expression of the photoaging-related proteins matrix metalloproteinases-1 and -9 and cyclooxygenase-2. As the lipophilicity of the P0 derivatives increased, their antioxidant potency increased, but more pronounced cytotoxic effects were also detected. In summary, P0 and P2 may be promising candidates for the prevention and treatment of UVB-induced skin photodamage and photoaging.


Assuntos
Senescência Celular/efeitos dos fármacos , Ésteres/química , Hidroxibenzoatos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Raios Ultravioleta , Animais , Antioxidantes/química , Antioxidantes/metabolismo , Linhagem Celular , Senescência Celular/efeitos da radiação , Ciclo-Oxigenase 2/metabolismo , Regulação para Baixo/efeitos dos fármacos , Fibroblastos/citologia , Hidroxibenzoatos/química , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos da radiação , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , NADPH Oxidases/metabolismo , Oxirredução , Estresse Oxidativo/efeitos da radiação , Substâncias Protetoras/química , Substâncias Protetoras/farmacologia , Espécies Reativas de Oxigênio/metabolismo
2.
Adv Exp Med Biol ; 1216: 55-64, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31894547

RESUMO

Chronic inflammation, which is called "inflamm-aging" , is characterized by an increased level of inflammatory cytokines in response to physiological and environmental stressors, and causes the immune system to function consistently at a low level, even though it is not effective. Possible causes of inflammaging include genetic susceptibility, visceral obesity, changes in gut microbiota and permeability, chronic infections and cellular senescence. Inflammation has a role in the development of many age-related diseases, such as frailty. Low grade chronic inflammation can also increase the risk of atherosclerosis and insulin resistance which are the leading mechanisms in the development of cardiovascular diseases (CVD). As it is well known that the risk of CVD is higher in older people with frailty and the risk of frailty is higher in patients with CVD, there may be relationship between inflammation and the development of CVD and frailty. Therefore, this important issue will be discussed in this chapter.


Assuntos
Doenças Cardiovasculares/complicações , Idoso Fragilizado , Fragilidade/complicações , Inflamação/complicações , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/imunologia , Envelhecimento/patologia , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/patologia , Senescência Celular , Citocinas/imunologia , Fragilidade/imunologia , Fragilidade/patologia , Humanos , Inflamação/imunologia , Inflamação/patologia
3.
Adv Exp Med Biol ; 1216: 79-86, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31894549

RESUMO

Frailty is a complex clinical syndrome, progressively described in the last thirty years, resulting from multiple impairments across many organs and systems and characterized by a reduction in physiological reserves and increased vulnerability to stressors, as well. Cardiovascular diseases (CVDs) are a common health problem in very old populations. Age-related changes occur throughout the body and in all organs, including the cardiovascular system. Cellular senescence links age-related CVDs and frailty by many mechanisms of particular interest in the aging biology and geriatric syndromes. Cellular senescence may represent the pivotal factor with its senescence-associated secretory phenotype (SASP) leading to systemic inflammation. In this context, SASP may represent the key element in the association between aging, frailty and the development of age-related CVDs.


Assuntos
Envelhecimento/patologia , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/patologia , Senescência Celular , Idoso Fragilizado , Fragilidade/complicações , Fragilidade/patologia , Idoso , Humanos , Inflamação/complicações , Inflamação/patologia
4.
Ecol Lett ; 23(2): 381-398, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31773847

RESUMO

Animal response to stressors such as harsh environmental conditions and demanding biological processes requires energy generated through increased mitochondrial activity. This results in the production of reactive oxygen species (ROS). In vitro and some in vivo studies suggest that oxidative damage of DNA caused by ROS is responsible for telomere shortening. Since telomere length is correlated with survival in many vertebrates, telomere loss is hypothesised to trigger cellular ageing and/ or to reflect the harshness of the environment an individual has experienced. To improve our understanding of stress-induced telomere dynamics in non-human vertebrates, we analysed 109 relevant studies in a meta-analytical framework. Overall, the exposure to possible stressors was associated with shorter telomeres or higher telomere shortening rate (average effect size = -0.16 ± 0.03). This relationship was consistent for all phylogenetic classes and for all a priori-selected stressor categories. It was stronger in the case of pathogen infection, competition, reproductive effort and high activity level, which emphasises their importance in explaining intraspecific telomere length variability and, potentially, lifespan variability. Interestingly, the association between stressor exposure and telomeres in one hand, and oxidative stress in the other hand, covaried, suggesting the implication of oxidative stress in telomere dynamics.


Assuntos
Encurtamento do Telômero , Telômero , Animais , Senescência Celular , Filogenia , Vertebrados
5.
Mar Genomics ; 49: 100717, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31680057

RESUMO

The blood of fish has a continuous age distribution of erythrocytes. The properties of young and old erythrocytes differ with young erythrocytes being functionally much more versatile than old erythrocytes, which have higher haemoglobin content. Factors which affect the formation and breakdown of erythrocytes are reviewed. Erythropoiesis in fish is largely similar to that in mammals. However, definitive erythrocytes are mainly formed in the anterior part of the kidney, and erythropoietin is secreted mainly from the heart. Senescence of erythrocytes in fish has not been studied in detail, and consecutively the factors causing aging of erythrocytes in man are discussed. A major factor causing aging of erythrocytes is oxidative stress, which is also a major effect of toxicants on fish erythrocytes. Consequently, apparent age distribution of circulating erythrocytes will be affected by environmental pollution. At present, it is completely unknown, if the changes in age distribution of erythrocytes play a role in pollutant responses or if the age distribution of erythrocytes is actively regulated during environmental adaptation.


Assuntos
Senescência Celular , Eritrócitos/citologia , Peixes , Animais , Meio Ambiente , Eritropoese , Estresse Oxidativo
6.
Cell Mol Life Sci ; 77(2): 213-229, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31414165

RESUMO

In contrast to the well-recognized replicative and stress-induced premature senescence of normal somatic cells, mechanisms and clinical implications of senescence of cancer cells are still elusive and uncertain from patient-oriented perspective. Moreover, recent years provided multiple pieces of evidence that cancer cells may undergo senescence not only in response to chemotherapy or ionizing radiation (the so-called therapy-induced senescence) but also spontaneously, without any external insults. Since the molecular nature of the latter process is poorly recognized, the significance of spontaneously senescent cancer cells for tumor progression, therapy effectiveness, and patient survival is purely speculative. In this review, we summarize the most up-to-date research regarding therapy-induced and spontaneous senescence of cancer cells, by delineating the most important discoveries regarding the occurrence of these phenomena in vivo and in vitro. This review provides data collected from studies on various cancer cell models, and the narration is presented from the broader perspective of the most critical findings regarding the senescence of normal somatic cells.


Assuntos
Senescência Celular/fisiologia , Neoplasias/patologia , Animais , Humanos
7.
Nat Rev Drug Discov ; 18(12): 901, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31780845
8.
BMC Bioinformatics ; 20(1): 599, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31747877

RESUMO

BACKGROUND: Cellular aging is best studied in the budding yeast Saccharomyces cerevisiae. As an example of a pleiotropic trait, yeast lifespan is influenced by hundreds of interconnected genes. However, no quantitative methods are currently available to infer system-level changes in gene networks during cellular aging. RESULTS: We propose a parsimonious mathematical model of cellular aging based on stochastic gene interaction networks. This network model is made of only non-aging components: the strength of gene interactions declines with a constant mortality rate. Death of a cell occurs in the model when an essential node loses all of its interactions with other nodes, and is equivalent to the deletion of an essential gene. Stochasticity of gene interactions is modeled using a binomial distribution. We show that the exponential increase of mortality rate over time can emerge from this gene network model during the early stages of aging.We developed a maximal likelihood approach to estimate three lifespan-influencing network parameters from experimental lifespans: t0, the initial virtual age of the network system; n, the average lifespan-influencing interactions per essential node; and R, the initial mortality rate. We applied this model to yeast mutants with known effects on replicative lifespans. We found that deletion of SIR2, FOB1, and HXK2 considerably altered the initial virtual age but not the average lifespan-influencing interactions per essential node, suggesting that these mutations mainly influence the reliability of gene interactions but not the overall configurations of gene networks.We applied this model to investigate replicative lifespans of yeast natural isolates. We estimated that the average number of lifespan-influencing interactions per essential node is 7.0 (6.1-8) and the average estimated initial virtual age is 45.4 (30.6-74) cell divisions in these isolates. We also found that t0 could potentially mediate the observed Strehler-Mildvan correlation in yeast natural isolates. CONCLUSIONS: Our theoretical model provides a parsimonious interpretation of experimental lifespan data from the perspective of gene networks. We hope that our work will stimulate more interest in developing network models to study aging as a pleiotropic trait.


Assuntos
Senescência Celular/genética , Redes Reguladoras de Genes , Modelos Genéticos , Saccharomyces cerevisiae/citologia , Saccharomyces cerevisiae/genética , Funções Verossimilhança , Mutação/genética , Fenótipo , Reprodutibilidade dos Testes , Saccharomyces cerevisiae/isolamento & purificação , Proteínas de Saccharomyces cerevisiae/metabolismo , Processos Estocásticos
9.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(9): 806-811, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31750822

RESUMO

Objective To explore the effect of tanshinone IIA (TSA) on hydrogen peroxide (H2O2)-induced senescence of human umbilical vein endothelial cells (HUVECs) and the underlying mechanism. Methods HUVECs were cultured in vitro and divided into the control group, model group and TSA group. The cells in the TSA group were pre-treated with TSA for 24 hours. H2O2 was used to induce cell senescence in the model and TSA groups. Transfection with SIRT1 siRNA was used for the knockdown of SIRT1 in HUVECs. CCK-8 assay was performed to detect cell viability. The expression levels of senescence-related proteins (P21 and P26), SIRT1, phosphorylated endothelial nitric oxide synthase (p-eNOS), and eNOS were detected by Western blot analysis. Senescence-associated ß-galactosidase (SA-ß-gal) staining was performed to evaluate cell senescence. Results Pretreatment with TSA at low concentrations (10, 20 and 40 µg/mL) for 24 hours did not affect cell viability, while high concentrations (80, 160 and 320 µg/mL) decreased cell viability significantly. In addition, 10, 20 and 40 µg/mL of TSA promoted H2O2-mediated cell viability of HUVECs in a concentration-dependent manner. Compared with the control group, the positive rate of SA-ß-gal staining in the model group increased, while the positive rate in the TSA group was significantly lower than that in the model group. The expression levels of P21 and P16 protein in the model group were higher than those in the control group, while SIRT1 and p-eNOS/eNOS were lower than those in the control group. Conversely, the expression of P21 and P16 proteins in the TSA group were lower than those in the model group, and SIRT1 and p-eNOS/eNOS were higher in the TSA group than those in the model group. Transfected with SIRT1 siRNA significantly down-regulated the expression of SIRT1 in HUVECs and the positive rate of SA-ß-gal staining was notably raised when SIRT1 was silenced in TSA-treated HUVECs. Conclusion TSA attenuates H2O2-induced endothelial cell senescence by activating SIRT1/eNOS signaling pathway.


Assuntos
/farmacologia , Senescência Celular , Óxido Nítrico Sintase Tipo III/metabolismo , Sirtuína 1/metabolismo , Células Cultivadas , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio , Transdução de Sinais
10.
Invest Ophthalmol Vis Sci ; 60(14): 4643-4651, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31682715

RESUMO

Purpose: Conjunctivochalasis (CCH) is a common ocular disease and has received extensive attention recently. However, its exact pathogenesis remains largely unknown. Owing to the high morbidity of CCH in older people, this study aimed to investigate whether cellular senescence contributes to CCH progression and the underlying mechanism. Methods: Loose conjunctival tissues from CCH patients (n = 13) and normal conjunctival tissues from age-matched persons (n = 12) were obtained and the fibroblasts were separately induced and obtained. Cellular senescence, and the expression of senescence-associated genes (p53 and p21) and p38 in CCH conjunctival tissues and normal controls, were determined by senescence-associated ß-galactosidase (SA-ß-Gal) staining and quantitative (q)RT-PCR, respectively. To explore the effects of p38 on cellular senescence in CCH fibroblasts, small interfering RNA (siRNA) targeting p38 (siP38) and p38-specific inhibitor SB203580 was performed in CCH fibroblasts. Then, cellular senescence, cell viability, reactive oxygen species (ROS) production, and gene expression were detected according to the corresponding methods. Results: CCH conjunctival tissues had significantly more senescent cells, evidenced by more SA-ß-Gal-positive cells, and higher expression of senescence-associated genes (p53 and p21) and p38. CCH fibroblasts transfected with siP38 or treated with SB203580 had obviously reduced numbers of senescent cells, decreased ROS production, and increased cell viability, as well as reduced expression of senescence-associated genes. Meanwhile, blocking p38 signaling decreased the expression of p53 and p21. Conclusions: Therefore, these findings indicate that cellular senescence might be a causative factor for CCH. P38 signaling might play an important role in the progress of cellular senescence in CCH fibroblasts via manipulation of p53/p21 signaling.


Assuntos
Senescência Celular/fisiologia , Doenças da Túnica Conjuntiva/enzimologia , Fibroblastos/enzimologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Western Blotting , Contagem de Células , Proliferação de Células , Células Cultivadas , Doenças da Túnica Conjuntiva/patologia , Inibidores Enzimáticos/farmacologia , Fibroblastos/efeitos dos fármacos , Humanos , Imidazóis/farmacologia , Piridinas/farmacologia , RNA Interferente Pequeno/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais , Superóxido Dismutase/metabolismo , beta-Galactosidase/metabolismo
11.
Cancer Immunol Immunother ; 68(12): 2015-2027, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31705171

RESUMO

The transformation and progression of myelodysplastic syndromes (MDS) to secondary acute myeloid leukemia (sAML) involve genetic, epigenetic, and microenvironmental factors. Driver mutations have emerged as valuable markers for defining risk groups and as candidates for targeted treatment approaches in MDS. It is also evident that the risk of transformation to sAML is increased by evasion of adaptive immune surveillance. This study was designed to explore the immune microenvironment, immunogenic tumor-intrinsic mechanisms (HLA and PD-L1 expression), and tumor genetic features (somatic mutations and altered karyotypes) in MDS patients and to determine their influence on the progression of the disease. We detected major alterations of the immune microenvironment in MDS patients, with a reduced count of CD4+ T cells, a more frequent presence of markers related to T cell exhaustion, a more frequent presence of myeloid-derived suppressor cells (MDSCs), and changes in the functional phenotype of NK cells. HLA Class I (HLA-I) expression was normally expressed in CD34+ blasts and during myeloid differentiation. Only two out of thirty-six patients with homozygosity for HLA-C groups acquired complete copy-neutral loss of heterozygosity in the HLA region. PD-L1 expression on the leukemic clone was also increased in MDS patients. Finally, no interplay was observed between the anti-tumor immune microenvironment and mutational genomic features. In summary, extrinsic and intrinsic immunological factors might severely impair immune surveillance and contribute to clonal immune escape. Genomic alterations appear to make an independent contribution to the clonal evolution and progression of MDS.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Células Matadoras Naturais/imunologia , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/genética , Células Supressoras Mieloides/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/metabolismo , Carcinogênese , Senescência Celular , Progressão da Doença , Feminino , Antígenos HLA-C/genética , Humanos , Vigilância Imunológica , Masculino , Pessoa de Meia-Idade , Mutação/genética , Evasão Tumoral , Microambiente Tumoral/imunologia , Adulto Jovem
12.
Adv Exp Med Biol ; 1192: 521-544, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31705512

RESUMO

Major psychiatric disorders are linked to early mortality and patients afflicted with these ailments demonstrate an increased risk of developing physical diseases that are characteristically seen in the elderly. Psychiatric conditions like major depressive disorder, bipolar disorder, and schizophrenia may be associated with accelerated cellular aging, indicated by shortened leukocyte telomere length (LTL), which could underlie this connection. Telomere shortening occurs with repeated cell division and is reflective of a cell's mitotic history. It is also influenced by cumulative exposure to inflammation and oxidative stress as well as the availability of telomerase, the telomere-lengthening enzyme. Precariously short telomeres can cause cells to undergo senescence, apoptosis, or genomic instability; shorter LTL correlates with compromised general health and foretells mortality. Important data specify that LTL may be reduced in principal psychiatric illnesses, possibly in proportion to exposure to the ailment. Telomerase, as measured in peripheral blood monocytes, has been less well characterized in psychiatric illnesses, but a role in mood disorder has been suggested by preclinical and clinical studies. In this manuscript, the most recent studies on LTL and telomerase activity in mood disorders are comprehensively reviewed, potential mediators are discussed, and future directions are suggested. An enhanced comprehension of cellular aging in psychiatric illnesses could lead to their re-conceptualizing as systemic ailments with manifestations both inside and outside the brain. At the same time, this paradigm shift could identify new treatment targets, helpful in bringing about lasting cures to innumerable sufferers across the globe.


Assuntos
Senescência Celular/genética , Leucócitos/metabolismo , Transtornos Mentais/genética , Telomerase , Telômero/metabolismo , Idoso , Humanos , Transtornos Mentais/diagnóstico , Homeostase do Telômero , Encurtamento do Telômero
13.
Cancer Immunol Immunother ; 68(12): 2041-2054, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31720814

RESUMO

Hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC) is usually considered an inflammation-related cancer associated with chronic inflammation triggered by exposure to HBV and tumor antigens. T-cell exhaustion is implicated in immunosuppression of chronic infections and tumors. Although immunotherapies that enhance immune responses by targeting programmed cell death-1(PD-1)/PD-L1 are being applied to malignancies, these treatments have shown limited response rates, suggesting that additional inhibitory receptors are also involved in T-cell exhaustion and tumor outcome. Here, we analyzed peripheral blood samples and found that coexpression of PD-1 and T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) was significantly upregulated on CD4+ and CD8+ T cells from patients with HBV-HCC compared with those from patients with chronic HBV or HBV-liver cirrhosis. Additionally, PD-1+ TIGIT+ CD8+ T-cell populations were elevated in patients with advanced stage and progressed HBV-HCC. Importantly, PD-1+ TIGIT+ CD8+ T-cell populations were negatively correlated with overall survival rate and progression-free survival rates. Moreover, we showed that PD-1+ TIGIT+ CD8+ T cells exhibit features of exhausted T cells, as manifested by excessive activation, high expression of other inhibitory receptors, high susceptibility to apoptosis, decreased capacity for cytokine secretion, and patterns of transcription factor expression consistent with exhaustion. In conclusion, PD-1+ TIGIT+ CD8+ T-cell populations are associated with accelerated disease progression and poor outcomes in HBV-HCC, which might not only have important clinical implications for prognosis but also provide a rationale for new targets in immunotherapy.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Carcinoma Hepatocelular/imunologia , Vírus da Hepatite B/fisiologia , Hepatite B/imunologia , Neoplasias Hepáticas/imunologia , Adulto , Carcinogênese , Carcinoma Hepatocelular/mortalidade , Senescência Celular/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Hepatite B/mortalidade , Humanos , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Receptor de Morte Celular Programada 1/metabolismo , Estudos Prospectivos , Receptores Imunológicos/metabolismo , Análise de Sobrevida
14.
Invest Ophthalmol Vis Sci ; 60(14): 4583-4595, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31675075

RESUMO

Purpose: Trabecular meshwork (TM) cells detect and coordinate responses to intraocular pressure (IOP) in the eye. TM cells become dysfunctional in glaucoma where IOP is often elevated. Recently, we showed that normal TM (NTM) cells communicate by forming tubular connections called tunneling nanotubes (TNTs). Here, we investigated TNTs in glaucomatous TM (GTM) cells. Methods: Primary GTM and NTM cells were established from cadaver eyes. Transfer of Vybrant DiO and DiD-labeled vesicles via TNT connections was measured. Imaris software measured the number and length of cell protrusions from immunofluorescent confocal images. Live-cell imaging of the actin cytoskeleton was performed. The distribution of myosin-X, a regulator of TNTs/filopodia, was investigated in TM cells and tissue. Results: GTM cells contained significantly more transferred fluorescent vesicles than NTM cells (49.6% vs. 35%). Although NTM cells had more protrusions at the cell surface than GTM cells (7.61 vs. 4.65 protrusions/cell), GTM protrusions were significantly longer (12.1 µm vs. 9.76 µm). Live-cell imaging demonstrated that the GTM actin cytoskeleton was less dynamic, and vesicle transfer between cells was significantly slower than NTM cells. Furthermore, rearrangement of the actin cortex adjacent to the TNT may influence TNT formation. Myosin-X immunostaining was punctate and disorganized in GTM cells and tissue compared to age-matched NTM controls. Conclusions: Together, our data demonstrate that GTM cells have phenotypic and functional differences in their TNTs. Significantly slower vesicle transfer via TNTs in GTM cells may delay the timely propagation of cellular signals when pressures become elevated in glaucoma.


Assuntos
Citoesqueleto de Actina/metabolismo , Glaucoma de Ângulo Aberto/patologia , Miosinas/metabolismo , Nanotubos , Pseudópodes/metabolismo , Malha Trabecular/patologia , Western Blotting , Tamanho Celular , Células Cultivadas , Senescência Celular/fisiologia , Densitometria , Glaucoma de Ângulo Aberto/metabolismo , Humanos , Microscopia Confocal , Fagocitose/fisiologia , Fenótipo , Transdução de Sinais/fisiologia , Malha Trabecular/metabolismo
15.
EMBO J ; 38(23): e101982, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31633821

RESUMO

Cellular senescence has been shown to contribute to skin ageing. However, the role of melanocytes in the process is understudied. Our data show that melanocytes are the only epidermal cell type to express the senescence marker p16INK4A during human skin ageing. Aged melanocytes also display additional markers of senescence such as reduced HMGB1 and dysfunctional telomeres, without detectable telomere shortening. Additionally, senescent melanocyte SASP induces telomere dysfunction in paracrine manner and limits proliferation of surrounding cells via activation of CXCR3-dependent mitochondrial ROS. Finally, senescent melanocytes impair basal keratinocyte proliferation and contribute to epidermal atrophy in vitro using 3D human epidermal equivalents. Crucially, clearance of senescent melanocytes using the senolytic drug ABT737 or treatment with mitochondria-targeted antioxidant MitoQ suppressed this effect. In conclusion, our study provides proof-of-concept evidence that senescent melanocytes affect keratinocyte function and act as drivers of human skin ageing.


Assuntos
Envelhecimento/patologia , Atrofia/patologia , Senescência Celular , Melanócitos/patologia , Pele/patologia , Telômero/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/efeitos dos fármacos , Atrofia/induzido quimicamente , Células Cultivadas , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Epiderme/efeitos dos fármacos , Epiderme/patologia , Feminino , Humanos , Masculino , Melanócitos/metabolismo , Pessoa de Meia-Idade , Comunicação Parácrina , Espécies Reativas de Oxigênio/metabolismo , Receptores CXCR4/metabolismo , Pele/metabolismo , Telômero/metabolismo , Adulto Jovem
16.
Nat Commun ; 10(1): 4731, 2019 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-31636264

RESUMO

Compounds with specific cytotoxic activity in senescent cells, or senolytics, support the causal involvement of senescence in aging and offer therapeutic interventions. Here we report the identification of Cardiac Glycosides (CGs) as a family of compounds with senolytic activity. CGs, by targeting the Na+/K+ATPase pump, cause a disbalanced electrochemical gradient within the cell causing depolarization and acidification. Senescent cells present a slightly depolarized plasma membrane and higher concentrations of H+, making them more susceptible to the action of CGs. These vulnerabilities can be exploited for therapeutic purposes as evidenced by the in vivo eradication of tumors xenografted in mice after treatment with the combination of a senogenic and a senolytic drug. The senolytic effect of CGs is also effective in the elimination of senescence-induced lung fibrosis. This experimental approach allows the identification of compounds with senolytic activity that could potentially be used to develop effective treatments against age-related diseases.


Assuntos
Apoptose/efeitos dos fármacos , Glicosídeos Cardíacos/farmacologia , Senescência Celular/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Células A549 , Animais , Antibióticos Antineoplásicos/farmacologia , Bleomicina/farmacologia , Neoplasias da Mama , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Digoxina/farmacologia , Feminino , Humanos , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Camundongos , Osteoartrite , Ouabaína/farmacologia , Proscilaridina/farmacologia , Fibrose Pulmonar , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Nat Neurosci ; 22(11): 1806-1819, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31636448

RESUMO

Prediabetes and Alzheimer's disease both increase in prevalence with age. The former is a risk factor for the latter, but a mechanistic linkage between them remains elusive. We show that prediabetic serum hyperinsulinemia is reflected in the cerebrospinal fluid and that this chronically elevated insulin renders neurons resistant to insulin. This leads to abnormal electrophysiological activity and other defects. In addition, neuronal insulin resistance reduces hexokinase 2, thus impairing glycolysis. This hampers the ubiquitination and degradation of p35, favoring its cleavage to p25, which hyperactivates CDK5 and interferes with the GSK3ß-induced degradation of ß-catenin. CDK5 contributes to neuronal cell death while ß-catenin enters the neuronal nucleus and re-activates the cell cycle machinery. Unable to successfully divide, the neuron instead enters a senescent-like state. These findings offer a direct connection between peripheral hyperinsulinemia, as found in prediabetes, age-related neurodegeneration and cognitive decline. The implications for neurodegenerative conditions such as Alzheimer's disease are described.


Assuntos
Envelhecimento/fisiologia , Ciclo Celular/fisiologia , Senescência Celular/fisiologia , Hiperinsulinismo/fisiopatologia , Resistência à Insulina/fisiologia , Neurônios/fisiologia , Animais , Morte Celular/fisiologia , Senescência Celular/efeitos dos fármacos , Quinase 5 Dependente de Ciclina/metabolismo , Potenciais Pós-Sinápticos Excitadores/fisiologia , Expressão Gênica/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Hexoquinase/metabolismo , Hiperinsulinismo/líquido cefalorraquidiano , Potenciais Pós-Sinápticos Inibidores/fisiologia , Insulina/farmacologia , Liraglutida/farmacologia , Masculino , Aprendizagem em Labirinto/fisiologia , Metformina/farmacologia , Camundongos , Neurônios/metabolismo , Fosfotransferases/metabolismo , Cultura Primária de Células , Proteínas Serina-Treonina Quinases/metabolismo , Ubiquitinação/fisiologia , beta Catenina/metabolismo
18.
Nature ; 574(7779): 553-558, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31645721

RESUMO

Age-associated chronic inflammation (inflammageing) is a central hallmark of ageing1, but its influence on specific cells remains largely unknown. Fibroblasts are present in most tissues and contribute to wound healing2,3. They are also the most widely used cell type for reprogramming to induced pluripotent stem (iPS) cells, a process that has implications for regenerative medicine and rejuvenation strategies4. Here we show that fibroblast cultures from old mice secrete inflammatory cytokines and exhibit increased variability in the efficiency of iPS cell reprogramming between mice. Variability between individuals is emerging as a feature of old age5-8, but the underlying mechanisms remain unknown. To identify drivers of this variability, we performed multi-omics profiling of fibroblast cultures from young and old mice that have different reprogramming efficiencies. This approach revealed that fibroblast cultures from old mice contain 'activated fibroblasts' that secrete inflammatory cytokines, and that the proportion of activated fibroblasts in a culture correlates with the reprogramming efficiency of that culture. Experiments in which conditioned medium was swapped between cultures showed that extrinsic factors secreted by activated fibroblasts underlie part of the variability between mice in reprogramming efficiency, and we have identified inflammatory cytokines, including TNF, as key contributors. Notably, old mice also exhibited variability in wound healing rate in vivo. Single-cell RNA-sequencing analysis identified distinct subpopulations of fibroblasts with different cytokine expression and signalling in the wounds of old mice with slow versus fast healing rates. Hence, a shift in fibroblast composition, and the ratio of inflammatory cytokines that they secrete, may drive the variability between mice in reprogramming in vitro and influence wound healing rate in vivo. This variability may reflect distinct stochastic ageing trajectories between individuals, and could help in developing personalized strategies to improve iPS cell generation and wound healing in elderly individuals.


Assuntos
Envelhecimento/metabolismo , Reprogramação Celular , Senescência Celular/fisiologia , Fibroblastos/metabolismo , Cicatrização , Animais , Linhagem Celular , Reprogramação Celular/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Citocinas/metabolismo , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/metabolismo , Mediadores da Inflamação/metabolismo , Judeus/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sequência de RNA , Transdução de Sinais/efeitos dos fármacos , Análise de Célula Única , Processos Estocásticos , Fatores de Tempo , Cicatrização/efeitos dos fármacos
19.
Invest Ophthalmol Vis Sci ; 60(13): 4436-4450, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31652328

RESUMO

Purpose: The purpose of this study was to systematically characterize and correlate the transcriptome and DNA methylome signatures of mouse Müller cells that may underlie the development, physiological functions, and regeneration capacity of these cells. Methods: Mouse Müller cells under normal, injury, and aging conditions were sorted from Müller cell-specific green fluorescent protein (GFP)-expressing mice. RNA sequencing was used to sequence transcriptomes, and reduced representation bisulfite sequencing was used to sequence DNA methylomes. Various bioinformatics tools were used to compare and correlate the transcriptomes and DNA methylomes. Results: Müller cells express a distinct transcriptome that is in line with their retinal supporting roles and dormant retinogenic status. Injury changes the Müller cell transcriptome dramatically but fails to stimulate the cell cycle machinery and retinogenic factors to the states observed in early retinal progenitor cells (RPCs). Müller cells exhibit a less methylated genome than that of early RPCs, but most regulatory elements for Müller cell- and RPC-specific genes are similarly hypomethylated in both Müller cells and RPCs, except for a subset of Müller cell-specific functional genes. Aging only subtly affects the transcriptome and DNA methylome of Müller cells. Conclusions: Failure to reactivate the cell cycle machinery and retinogenic factors to necessary levels might be key barriers blocking Müller cells from entering an RPC-like regeneration state. DNA methylation might regulate the expression of a subset of Müller cell-specific functional genes during development but is likely not involved in restricting the regeneration activity of Müller cells.


Assuntos
Senescência Celular/fisiologia , Células Ependimogliais/metabolismo , Traumatismos Oculares/metabolismo , Neuroglia/metabolismo , Retina/lesões , Transcriptoma/genética , Animais , Ilhas de CpG/genética , Metilação de DNA , Citometria de Fluxo , Camundongos , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase , Regeneração/fisiologia , Células-Tronco/metabolismo
20.
Nature ; 574(7780): 635-636, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31659315
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